in silicoとロボットによる創薬支援システムの開発とシャーガス病治療薬探索

2023 Fiscal Year Annual Research Report

• Project/Area Number: 20H00620
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: 関嶋 政和 東京工業大学, 情報理工学院, 准教授 (80371053)
• Co-Investigator(Kenkyū-buntansha): 稲岡 健ダニエル 長崎大学, 熱帯医学研究所, 准教授 (10623803) ; 庄司 満 横浜薬科大学, 薬学部, 教授 (30339139) ; 平山 謙二 長崎大学, 熱帯医学・グローバルヘルス研究科, 教授 (60189868) ; 樺島 祥介 東京大学, 大学院理学系研究科(理学部), 教授 (80260652)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: AI創薬 / 抗規制原虫薬 / 機械学習 / ロボット / ケモインフォマティクス / バイオインフォマティクス

Outline of Annual Research Achievements

創薬では、薬候補化合物は標的蛋白質との結合親和性だけでなく、毒性や代謝などを考慮したより薬らしく最適化が行われていく。今年度は、機械学習の多目的最適化を考慮した化合物生成手法とパレートフロントからの化合物選択手法が完成したため、分担者の稲岡教授がアッセイ系を持つトリパノソーマ寄生原虫の治療薬の標的となる TAO（トリパノチオン酸化還元酵素）を最初の標的標的蛋白質として、結合親和性とQEDの双方を多目的最適化した化合物の生成を合成経路付きで行った。ドッキングスコアと薬らしさ（QED）、毒性を重み付きの総和や総乗する手法と異なり、化合物を見ながらパレートフロントから化合物を選択可能である。更に実際に合成を行う為に合成化学者と連携して機械学習による逆合成解析ツールを用いてトップ10の化合物のウェットでの実験を試み、それにより実験からのフィードバックが得られ、生成モデルの生成時のプロトコールの改善に繋がった。本研究で開発した手法をオープンソース化し、GitHub で公開した。これにより、他の研究者が本手法を利用し、さらなる発展を遂げることが期待される。本研究で得られた知見は、創薬研究におけるAI の活用方法に関する議論を深める上でも重要である。

Research Progress Status

令和5年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和5年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Fumarate respiration of Fasciola flukes as a potential drug target (2024)
  • Author(s): Tashibu Atsushi、Inaoka Daniel Ken、Sakamoto Kimitoshi、Murakami Kenji、Zannatul Ferdoush、Kita Kiyoshi、Ichikawa-Seki Madoka
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 13 Pages: -
  • DOI: 10.3389/fcimb.2023.1302114
  • Peer Reviewed / Open Access
• [Journal Article] Generating Gradients in the Energy Landscape Using Rectified Linear Type Cost Functions for Efficiently Solving 0/1 Matrix Factorization in Simulated Annealing (2024)
  • Author(s): Konoshima Makiko、Tamura Hirotaka、Kabashima Yoshiyuki
  • Journal Title: Journal of the Physical Society of Japan Volume: 93 Pages: 1-7
  • DOI: 10.7566/JPSJ.93.044002
  • Peer Reviewed
• [Journal Article] PRA-Pred: Structure-based prediction of protein-RNA binding affinity (2024)
  • Author(s): Harini K.、Sekijima M.、Gromiha M. Michael
  • Journal Title: International Journal of Biological Macromolecules Volume: 259 Pages: 129490～129490
  • DOI: 10.1016/j.ijbiomac.2024.129490
  • Peer Reviewed
• [Journal Article] Aspects for development of novel antibacterial medicines using a vitamin D3 decomposition product in Helicobacter pylori infection (2023)
  • Author(s): Wanibuchi Kiyofumi、Hosoda Kouichi、Amgalanbaatar Avarzed、Ihara Masato、Takezawa Motoki、Sakai Yuki、Masui Hisashi、Shoji Mitsuru、Hayashi Shunji、Shimomura Hirofumi
  • Journal Title: The Journal of Antibiotics Volume: 76 Pages: 665～672
  • DOI: 10.1038/s41429-023-00651-w
  • Peer Reviewed
• [Journal Article] Development of polymer-immobilised acridinium catalyst and its application in photoinduced 1,4-addition to α,β-unsaturated carbonyl compounds (2023)
  • Author(s): Umezawa Misaki、Aoki Shoji、Okuno Yoshinori、Sato Yasuo、Wanibuchi Kiyofumi、Shoji Mitsuru
  • Journal Title: Tetrahedron Letters Volume: 128 Pages: 154698～154698
  • DOI: 10.1016/j.tetlet.2023.154698
  • Peer Reviewed
• [Journal Article] Challenges Based on Antiplasmodial and Antiviral Activities of 7‐Chloro‐4‐aminoquinoline Derivatives (2023)
  • Author(s): Mizuta Satoshi、Mosaddeque Farhana、Tun Mya Myat Ngwe、Teklemichael Awet Alem、Taniguchi Mayumi、Hosokawa Masashi、Yamaguchi Tomoko、Makau Juliann、Huy Nguyen Tien、Mizukami Shusaku、Nishida Noriyuki、Morita Kouichi、Hirayama Kenji
  • Journal Title: ChemMedChem Volume: 18 Pages: -
  • DOI: 10.1002/cmdc.202200586
  • Peer Reviewed
• [Journal Article] Anti-Trypanosoma cruzi activity of Coptis rhizome extract and its constituents (2023)
  • Author(s): Tayama Yuki、Mizukami Shusaku、Toume Kazufumi、Komatsu Katsuko、Yanagi Tetsuo、Nara Takeshi、Tieu Paul、Huy Nguyen Tien、Hamano Shinjiro、Hirayama Kenji
  • Journal Title: Tropical Medicine and Health Volume: 51 Pages: -
  • DOI: 10.1186/s41182-023-00502-2
  • Peer Reviewed / Open Access
• [Journal Article] Biochemical characterization and identification of ferulenol and embelin as potent inhibitors of malate:quinone oxidoreductase from Campylobacter jejuni (2023)
  • Author(s): Kabongo Augustin Tshibaka、Acharjee Rajib、Sakura Takaya、Bundutidi Gloria Mavinga、Hartuti Endah Dwi、Davies Cadi、Gundogdu Ozan、Kita Kiyoshi、Shiba Tomoo、Inaoka Daniel Ken
  • Journal Title: Frontiers in Molecular Biosciences Volume: 10 Pages: 1-14
  • DOI: 10.3389/fmolb.2023.1095026
  • Peer Reviewed / Open Access
• [Journal Article] Compressed Sensing Radar Detectors Under the Row-Orthogonal Design Model: A Statistical Mechanics Perspective (2023)
  • Author(s): Na Siqi、Huang Tianyao、Liu Yimin、Takahashi Takashi、Kabashima Yoshiyuki、Wang Xiqin
  • Journal Title: IEEE Transactions on Signal Processing Volume: 71 Pages: 2668～2682
  • DOI: 10.1109/TSP.2023.3297743
  • Peer Reviewed
• [Journal Article] Decision Theoretic Cutoff and ROC Analysis for Bayesian Optimal Group Testing (2023)
  • Author(s): Sakata Ayaka、Kabashima Yoshiyuki
  • Journal Title: IEEE Transactions on Information Theory Volume: 69 Pages: 5902～5920
  • DOI: 10.1109/tit.2023.3276696
  • Peer Reviewed
• [Journal Article] Average case analysis of Lasso under ultra sparse conditions (2023)
  • Author(s): Koki Okajima, Xiangming Meng, Takashi Takahashi, Yoshiyuki Kabashima
  • Journal Title: Proceedings of The 26th International Conference on Artificial Intelligence and Statistics (PMLR206) Volume: - Pages: 11317-11330
  • Peer Reviewed
• [Journal Article] On Model Selection Consistency of Lasso for High-Dimensional Ising Models (2023)
  • Author(s): Xiangming Meng, Tomoyuki Obuchi, Yoshiyuki Kabashima
  • Journal Title: Proceedings of The 26th International Conference on Artificial Intelligence and Statistics (PMLR206) Volume: - Pages: 6783-6805
  • Peer Reviewed
• [Journal Article] Gargoyles: An Open Source Graph-Based Molecular Optimization Method Based on Deep Reinforcement Learning (2023)
  • Author(s): Erikawa Daiki、Yasuo Nobuaki、Suzuki Takamasa、Nakamura Shogo、Sekijima Masakazu
  • Journal Title: ACS Omega Volume: 8 Pages: 37431～37441
  • DOI: 10.1021/acsomega.3c05430
  • Peer Reviewed
• [Journal Article] Enhancing the Performance of AlphaFold Through Modified Storage Method and Optimization of HHblits on TSUBAME3.0 Supercomputer (2023)
  • Author(s): Fujita Hayato、Nomura Akihiro、Endo Toshio、Sekijima Masakazu
  • Journal Title: Proceedings of the 2023 Congress in Computer Science, Computer Engineering, & Applied Computing (CSCE) Volume: - Pages: 2140-2146
  • DOI: 10.1109/CSCE60160.2023.00351
  • Peer Reviewed
• [Journal Article] Predicting Chemical Reaction Product by Graph Transformer (2023)
  • Author(s): Makino Shunya、Yasuo Nobuaki、Sekijima Masakazu
  • Journal Title: Proceedings of the 2023 Congress in Computer Science, Computer Engineering, & Applied Computing (CSCE) Volume: - Pages: 2147-2152
  • DOI: 10.1109/CSCE60160.2023.00352
  • Peer Reviewed
• [Journal Article] Discovery of a Hidden Trypanosoma cruzi Spermidine Synthase Binding Site and Inhibitors through In Silico, In Vitro, and X-ray Crystallography (2023)
  • Author(s): Yoshino Ryunosuke、Yasuo Nobuaki、Hagiwara Yohsuke、Ishida Takashi、Inaoka Daniel Ken、Amano Yasushi、Tateishi Yukihiro、Ohno Kazuki、Namatame Ichiji、Niimi Tatsuya、Orita Masaya、Kita Kiyoshi、Akiyama Yutaka、Sekijima Masakazu
  • Journal Title: ACS Omega Volume: 8 Pages: 25850～25860
  • DOI: 10.1021/acsomega.3c01314
  • Peer Reviewed / Open Access
• [Presentation] Compressed sensing based on diffusion models (2023)
  • Author(s): Yoshiyuki Kabashima
  • Organizer: ICTP Trieste
  • Int'l Joint Research / Invited
• [Presentation] Replica analysis of Lasso for ultra-sparse signals (2023)
  • Author(s): Yoshiyuki Kabashima
  • Organizer: East Asia Joint Seminar on Statistical Physics
  • Int'l Joint Research / Invited
• [Presentation] 大自由度システムの統計学としての統計力学 (2023)
  • Author(s): 樺島祥介
  • Organizer: 2024年第71回応用物理学会春季学術講演会
  • Invited
• [Presentation] 拡散モデルに基づく圧縮センシング (2023)
  • Author(s): 樺島祥介
  • Organizer: 第52回情報計測オンラインセミナー
  • Invited
• [Presentation] Knowledge, Attitude, and Practice of Mothers toward Chagas disease in La Guardia, Santa Cruz Department, Bolivia: A Cross-sectional Study (2023)
  • Author(s): Takehara Y, Trang TBL, Makram AM, Rashidul Hashan M, Altom A, Thanh VN, Elsheikh R, Iglesias-Rodriguez IM, Guzman Lijeron AY, Soria Medina NM, Quiroga Alpiri BN, Nishizawa JE, Huy NT, Hirayama K.
  • Organizer: Annual meeting of American Society of Tropical Medicine and Hygiene 2023
  • Int'l Joint Research
• [Presentation] Risk factors for mother-to-child transmission of Trypanosoma cruzi and Hepatitis B in the cross-border area of Argentina and Paraguay (2023)
  • Author(s): Takahashi Y, Avila S, Correa S, Cardone K, Fernandez M, Crudo F, Sato M, Aiga H, Hirayama K, Periago MV.
  • Organizer: Annual meeting of American Society of Tropical Medicine and Hygiene 2023
  • Int'l Joint Research
• [Presentation] Trypanosomal ASCT and alternative oxidase as tools to study Mycobacterium bioenergetics (2023)
  • Author(s): Mavinga Gloria Bundutidi, Ando Yuri, Matsuo Yuichi, Hayashishita Mizuki, Mochizuki Kota, Cook Gregory M., Sekijima Masakazu, Sakura Takaya, Hamano Shinjiro, Hirayama Kenji, Kita Kiyoshi, Ken Daniel Inaoka
  • Organizer: 11th Meeting GlycoNov/AdipoTryp
  • Int'l Joint Research
• [Presentation] Expression of an active ASCT/SCS cycle in Mycobacterium smegmatis confers resistance to Bedaquiline (2023)
  • Author(s): Mavinga Gloria Bundutidi, Ando Yuri, Matsuo Yuichi, Hayashishita Mizuki, Mochizuki Kota, Cook Gregory M., Sekijima Masakazu, Sakura Takaya, Hamano Shinjiro, Hirayama Kenji, Kita Kiyoshi, Ken Daniel Inaoka
  • Organizer: Gordon Research Conferences on Bioenergetics, Proctor Academy, New Hampshire
  • Int'l Joint Research / Invited
• [Presentation] Structural insights into SCOT activity of TbASCT-D62N mutant (2023)
  • Author(s): Ken Daniel Inaoka, Mochizuki Kota, Balogun Emmanuel O., Fukuda Keisuke, Kurasawa Hana, Shiba Tomoo, Harada Shigeharu, Maze Muriel, Millerioux Yoann, Bringaud Frederic, Boshar Michael, Hirayama Kenji, Kita Kiyoshi
  • Organizer: 11th Meeting GlycoNov/AdipoTryp
  • Int'l Joint Research
• [Presentation] The trypanosome alternative oxidase as a target for drug development (2023)
  • Author(s): Ken Daniel Inaoka
  • Organizer: Seminars in Pharmasciences
  • Int'l Joint Research
• [Presentation] Efficiency Improvements in Drug Discovery through Machine Learning and the Challenges to Overcome (2023)
  • Author(s): Masakazu Sekijima
  • Organizer: CBI学会2023年大会
• [Presentation] Development of hit-to-lead molecular optimization by multi-objective Monte Carlo Tree Search (2023)
  • Author(s): Takamasa SUZUKI, Nobuaki YASUO, Masakazu Sekijima
  • Organizer: CBI学会2023年大会
• [Presentation] パレート最適を考慮したHit-to-Leadにおける多目的最適化手法の開発 (2023)
  • Author(s): 鈴木敬将・安尾信明・関嶋政和
  • Organizer: 情報処理学会 第143回MPS・第74回BIO合同研究発表会
• [Presentation] タンパク質ーリガンド結合部位の特徴量化の改善に関する研究 (2023)
  • Author(s): 塩澤理紗・安尾信明・関嶋政和
  • Organizer: 情報処理学会 第143回MPS・第74回BIO合同研究発表会
• [Remarks] Mothra
  • URL: https://github.com/sekijima-lab/Mothra